Substituted dihydro 3-halo-1h-pyrazole-5-carboxylates their preparation and use

ABSTRACT

This invention relates to a compound of Formula I, a method for its preparation and its use in the preparation of a compound of Formula II wherein R 1 , R 2 , R 3 , X and n are as defined in the disclosure. This invention also discloses preparation of compounds of Formula III wherein R 1 , R 2 , R 6 , R 7 , R 8  and n are as defined in the disclosure. Also disclosed are certain intermediates of Formula 4 for the preparation of compounds of Formula I wherein X is N and R 2 , R 3  and n are as defined in the disclosure.

FIELD OF THE INVENTION

[0001] This invention relates to novel carboxylic acid derivatives of3-halo-1-aryl-substituted dihydro-1H-pyrazoles and pyrazoles. Thesecompounds are useful for preparation of certain anthranilic amidecompounds that are of interest as insecticides (see e.g. PCT PublicationWO 01/070671).

BACKGROUND OF THE INVENTION

[0002]Tetrahedron Letters, 1999, 40, 2605-2606 discloses preparation of1-phenyl-3-bromopyrazole-5-carboxylic acid derivatives involvinggeneration of a reactive bromonitrilimine intermediate. Cycloaddition ofthis intermediate with an acrylic ester gives a1-phenyl-3-bromo-2-pyrazoline-5-carboxylate ester, which can besubsequently oxidized to the desired1-phenyl-3-bromo-2-pyrazole-5-carboxylate ester. Alternatively,cycloaddition with a propiolate ester gives the1-phenyl-3-bromo-2-pyrazole-5-carboxylate ester directly.

[0003] U.S. Pat. No. 3,153,654 discloses condensation of certainoptionally substituted aryl (e.g. phenyl or naphthyl which areoptionally substituted with lower alkyl, lower alkoxy or halogen)hydrazines with certain fumaric or maleic esters to provide3-pyrazolidinone carboxylic acid derivatives.

[0004] Japanese Unexamined Patent Publications 9-316055 and 9-176124disclose production of pyrazole carboxylic acid ester derivatives andpyrazoline derivatives, respectively, which are substituted with alkylat the 1-position.

[0005]J. Med. Chem. 2001, 44, 566-578 discloses a preparation of1-(3-cyanophenyl)-3-methyl-1H-pyrazol-5-carboxylic acid and its use inpreparing inhibitors of blood coagulation factor Xa.

[0006] The present invention provides technology useful for convenientlypreparing 3-halo-5-carboxylate-1-aryl-substituted dihydro-1H-pyrazolesand pyrazoles.

SUMMARY OF THE INVENTION

[0007] This invention relates to a compound of Formula I

[0008] wherein

[0009] R¹ is halogen;

[0010] each R² is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₃-C₆(alkyl)cycloalkylamino, C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl;

[0011] R³ is H or C₁-C₄ alkyl;

[0012] X is N or CR⁴;

[0013] R⁴ is H or R²; and

[0014] n is 0 to 3, provided when X is CH then n is at least 1,

[0015] This invention also relates to a method for preparing a compoundof Formula I comprising (1) treating a compound of Formula 4

[0016] (wherein X, R², and n are as described above for Formula I and R³is C₁-C₄ alkyl) with a halogenating agent to form a compound of FormulaI; and when preparing compounds of Formula I wherein R³ is H, (2)converting the compound formed in (1) to a compound wherein R³ is H.

[0017] This invention also relates to a compound of Formula II

[0018] wherein R¹ is halogen (and X R², R³ and n are defined as abovefor Formula I) and a method of preparing a compound of Formula II. Themethod comprises (3) treating a compound of Formula I with an oxidant,optionally in the presence of an acid, to form a compound of Formula II;and when a compound of Formula I wherein R³ is C₁-C₄ alkyl is used toprepare a compound of Formula II wherein R³ is H, (4) converting thecompound formed in (2) to a compound of Formula II wherein R³ is H.

[0019] This invention also provides compounds of Formula 4 wherein X isN, and their use in preparing compounds of Formulae I and II, wherein Xis N (and R², R³ and n are defined as above for Formula I).

[0020] This invention also involves a method of preparing a compound ofFormula III,

[0021] wherein X, R¹, R², and n are defined as above for Formula II; R⁶is CH₃, Cl or Br; R⁷ is F, Cl, Br, I or CF₃; and R⁸ is C₁-C₄ alkyl,using a compound of Formula II wherein R⁶ is H. This method ischaracterized by preparing the compound of Formula II by the method asindicated above.

DETAILED DESCRIPTION OF THE INVENTION

[0022] In the above recitations, the term “alkyl”, used either alone orin compound words such as “alkylthio” or “haloalkyl” includesstraight-chain or branched alkyl, such as methyl, ethyl, n-propyl,i-propyl, or the different butyl, pentyl or hexyl isomers. “Alkenyl” caninclude straight-chain or branched alkenes such as 1-propenyl,2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.“Alkenyl” also includes polyenes such as 1,2-propadienyl and2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynessuch as 1-propynyl, 2-propynyl and the different butynyl, pentynyl andhexynyl isomers. “Alkynyl” can also include moieties comprised ofmultiple triple bonds such as 2,5-hexadiynyl. “Alkoxy” includes, forexample, methoxy, ethoxy, n-propyloxy, isopropyloxy and the differentbutoxy, pentoxy and hexyloxy isomers. “Alkoxyalkyl” denotes alkoxysubstitution on alkyl. Examples of “alkoxyalkyl” include CH₃OCH₂,CH₃OCH₂CH₂, CH₃CH₂OCH₂, CH₃CH₂CH₂CH₂OCH₂ and CH₃CH₂OCH₂CH₂.“Alkylthio”includes branched or straight-chain alkylthio moieties suchas methylthio, ethylthio, and the different propylthio, butylthio,pentylthio and hexylthio isomers. “Cycloalkyl” includes, for example,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. “Cycloalkylalkyl”indicates an alkyl group substituted with a cycloalky group andincludes, for example, cyclopropylmethyl, cyclobutylethyl,cyclopentylpropyl and cyclohexylmethyl. “Cycloalkylamino” means theamino nitrogen atom is attached to a cycloalkyl radical and a hydrogenatom and includes groups such as cyclopropylamino, cyclobutylamino,cyclopentylamino and cyclohexylamino. “(Alkyl)cycloalkylamino” means acycloalkylamino group where the hydrogen atom is replaced by an alkylradical; examples include groups such as (alkyl)cyclopropylamino,(alkyl)cyclobutylamino, (alkyl)cyclopentylamino and(alkyl)cyclohexylamino. Preferably the alkyl in (alkyl)cycloalkylaminois C₁-C₄ alkyl, while the cycloalkyl in cycloalkylamino and(alkyl)cycloalkylamino is C₃-C₆ cycloalkyl.

[0023] The term in this application “aryl” refers to an aromatic ring orring system or a heteroaromatic ring or ring system, each ring or ringsystem optionally substituted. The term “aromatic ring system” denotesfully unsaturated carbocycles and heterocycles in which at least onering of a polycyclic ring system is aromatic. Aromatic indicates thateach of ring atoms is essentially in the same plane and has a p-orbitalperpendicular to the ring plane, and in which (4n+2) π electrons, when nis 0 or a positive integer, are associated with the ring to comply withHüickel's rule. The term “aromatic carbocyclic ring system” includesfully aromatic carbocycles and carbocycles in which at least one ring ofa polycyclic ring system is aromatic (e.g. phenyl and naphthyl). Theterm “heteroaromatic ring or ring system” includes fully aromaticheterocycles and heterocycles in which at least one ring of a polycyclicring system is aromatic and in which at least one ring atom is notcarbon and can contain 1 to 4 heteroatoms independently selected fromthe group consisting of nitrogen, oxygen and sulfur, provided that eachheteroaromatic ring contains no more than 4 nitrogens, no more than 2oxygens and no more than 2 sulfurs (where aromatic indicates that theHüickel rule is satisfied). The heterocyclic ring systems can beattached through any available carbon or nitrogen by replacement of ahydrogen on said carbon or nitrogen. More specifically, the term “aryl”refers to the moiety

[0024] wherein R² and n are defined as above and the “3” indicates the3-position for substituents on the moiety.

[0025] The term “halogen”, either alone or in compound words such as“haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further,when used in compound words such as “haloalkyl”, said alkyl may bepartially or fully substituted with halogen atoms which may be the sameor different. Examples of “haloalkyl” include F₃C, ClCH₂, CF₃CH₂ andCF₃CCl₂. The terms “haloalkenyl”, “aloalkynyl”, “haloalkoxy”, and thelike, are defined analogously to the term “haloalkyl”. Examples of“aloalkenyl” include (Cl)₂C═CHCH₂ and CF₃CH₂CH═CHCH₂. Examples of“haloalkynyl” include HC≡CCHCl, CF₃C≡C, CCl₃C≡C and FCH₂C≡CCH₂. Examplesof “haloalkoxy” include CF₃O , CCl₃CH₂O , HCF₂CH₂CH₂O and CF₃CH₂O .

[0026] Examples of “alkylcarbonyl” include C(O)CH₃, C(O)CH₂CH₂CH₃ andC(O)CH(CH₃)₂. Examples of “alkoxycarbonyl” include CH₃OC(═O),CH₃CH₂OC(═O), CH₃CH₂CH₂OC(═O), (CH₃)₂CHOC(═O) and the different butoxy-or pentoxycarbonyl isomers. The terms “alkylaminocarbonyl” and“dialkylaminocarbonyl” include, for example, CH₃NHC(═O), CH₃CH₂NHC(═O)and (CH₃)₂NC(═O).

[0027] The total number of carbon atoms in a substituent group isindicated by the “C_(i)-C_(j)” prefix where i and j are numbers from 1to 8, For example, C₁-C₃ alkysulfonyl designates methylsulfonyl throughpropylsulfonyl. In the above recitations, when a compound of Formula Icontains a heteroaromatic ring, all substituents are attached to thisring through any available carbon or nitrogen by replacement of ahydrogen on said carbon or nitrogen.

[0028] When a group contains a substituent which can be hydrogen, forexample R⁴, then, when this substituent is taken as hydrogen, it isrecognized that this is equivalent to said group being unsubstituted.

[0029] Certain compounds of this invention can exist as one or morestereoisomers. The various stereoisomers include enantiomers,diastereomers, atropisomers and geometric isomers. One skilled in theart will appreciate that one stereoisomer may be more active and/or mayexhibit beneficial effects when enriched relative to the otherstereoisomer(s) or when separated from the other stereoisomer(s).Additionally, the skilled artisan knows how to separate, enrich, and/orto selectively prepare said stereoisomers. Accordingly, the compounds ofthe invention may be present as a mixture of stereoisomers, individualstereoisomers, or as an optically active form.

[0030] Preferred for cost, ease of synthesis and/or greatest utilityare:

[0031] Preferred 1. Compounds of Formula I wherein

[0032] R¹ is Cl or Br;

[0033] each R² is independently Cl or Br, and one R² is at the3-position; and

[0034] X is N.

[0035] Preferred 2. Compounds of Formula I wherein

[0036] R¹ is Cl or Br;

[0037] X is N; and

[0038] n is 0.

[0039] Of note are compounds of Formula I (including but not limited toPreferred 1) wherein n is 1 to 3.

[0040] Preferred 3. Compounds of Formula II wherein

[0041] X is N.

[0042] Preferred 4. Compounds of Formula II wherein

[0043] R¹ is Cl or Br;

[0044] each R² is independently Cl or Br, and one R² is at the3-position; and

[0045] X is N.

[0046] Preferred 5. Compounds of Formula II wherein

[0047] R¹ is Cl or Br;

[0048] X is N; and

[0049] n is 0.

[0050] Of note are compounds of Formula II (including but not limited toPreferred 3 and Preferred 4) wherein n is 1 to 3.

[0051] Preferred 6. Compounds of Formula 4 (wherein R³ is C₁-C₄ alkyl)wherein each

[0052] R² is independently Cl or Br, and one R² is at the 3-position.

[0053] Preferred 7. Compounds of Formula 4 (wherein R³ is C₁-C₄ alkyl)wherein

[0054] X is N; and

[0055] n is 0.

[0056] Of note are compounds of Formula 4 (wherein R³ is C₁-C₄ alkyl)including but not limited to Preferred 6, wherein n is 1 to 3.

[0057] The 3-position is identified by the “3” shown in the aryl moietyincluded in Formula I, Formula II and Formula 4 above.

[0058] Of note are compounds of Formula II wherein when R¹ is Cl or Br,n is 1, and R² selected from Cl or Br is at the 3-position; then X is N.Included are compounds wherein n is from 1 to 3.

[0059] Of note are compounds of Formula II wherein when R¹ is Cl or Br,n is 1, and R² selected from Cl or Br is at the 3-position; then X isCR⁴. Included are compounds wherein n is from 1 to 3.

[0060] Preferred methods are those comprising the preferred compoundsabove. Methods of note are those comprising the compounds of note above.Of particular note are a method of preparing a compound of Formula Iwherein n is from 1 to 3; and a method of preparing a compound ofFormula II wherein n is from 1 to 3.

[0061] A stepwise process of preparing compounds of Formula I andFormula II provided herein comprises (a) treating a compound of Formula2

[0062] with a compound of Formula 3

R³O₂CHC═CHCO₂R³

[0063] wherein R³ is C₁-C₄ alkyl,

[0064] in the presence of a base, to form a compound of Formula 4

[0065] wherein X, R² and n are defined as above and R³ is H or C₁-C₄alkyl. The compound of Formula 4 wherein R³ is C₁-C₄ alkyl can then be(1) treated with a halogenating agent to form a compound of Formula I;and when preparing compounds of Formula I wherein R³ is H (2) convertingthe compound formed in (1) to a compound wherein R³ is H.

[0066] The compound of Formula I prepared in (1) or (2) can then be (3)treated with an oxidant, optionally in the presence of an acid, to forma compound of Formula II; and when compounds of Formula I wherein R³ isC₁-C₄ alkyl are used to prepare compounds of Formula II wherein R³ is H,(4) converting the compound formed in (3) to a compound of Formula IIwherein R³ is H

[0067] Scheme 1 illustrates step (a).

[0068] In step (a), a compound of Formula 2 is treated with a compoundof Formula 3 wherein R³ is C₁-C₄ alkyl (a fumarate ester or maleateester or a mixture thereof may be used) in the presence of a base and asolvent. The base is typically a metal alkoxide salt, such as sodiummethoxide, potassium methoxide, sodium ethoxide, potassium ethoxide,potassium tert-butoxide, lithium tert-butoxide, and the like. Greaterthan 0.5 equivalents of base versus the compound of Formula 2 should beused, preferably between 0.9 and 1.3 equivalents. Greater than 1.0equivalents of the compound of Formula 3 should be used, preferablybetween 1.0 to 1.3 equivalents. Polar protic and polar aprotic organicsolvents can be used, such as alcohols, acetonitrile, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide and the like. Preferredsolvents are alcohols such as methanol and ethanol. It is especiallypreferred that the alcohol be the same as that making up the fumarate ormaleate ester and the alkoxide base. The reaction is typically conductedby mixing the compound of Formula 2 and the base in the solvent. Themixture can be heated or cooled to a desired temperature and thecompound of Formula 3 added over a period of time. Typically reactiontemperatures are between 0° C. and the boiling point of the solventused. The reaction may be conducted under greater than atmosphericpressure in order to increase the boiling point of the solvent.Temperatures between about 30 and 90° C. are generally preferred. Theaddition time can be as quick as heat transfer allows. Typical additiontimes are between 1 minute and 2 hours. Optimum reaction temperature andaddition time vary depending upon the identities of the compounds ofFormula 2 and Formula 3. After addition, the reaction mixture can beheld for a time at the reaction temperature. Depending upon the reactiontemperature, the required hold time may be from 0 to 2 hours. Typicalhold times are from about 10 to 60 minutes. The reaction mass then canbe acidified by adding an organic acid, such as acetic acid and thelike, or an inorganic acid, such as hydrochloric acid, sulfuic acid andthe like. Depending on the reaction conditions and the means ofisolation, compounds of Formula 4 wherein R³ is H or compounds ofFormula 4 wherein R³ is C₁-C₄ alkyl can be prepared. For example, acompound of Formula 4 wherein R³ is C₁-C₄ alkyl can be hydrolyzed insitu to a compound of Formula 4 wherein R³ is H when water is present inthe reaction mixture. Compounds of Formula 4 wherein R³ is H can bereadily transformed to compounds of Formula 4 wherein R³ is C₁-C₄ alkylusing esterification methods well-known in the art. Compounds of Formula4 wherein R³ is C₁-C₄ alkyl are preferred. The desired product, acompound of Formula 4, can be isolated by methods known to those skilledin the art, such as crystallization, extraction or distillation.

[0069] In step (1) as illustrated in Scheme 2, a compound of Formula 4is treated with a halogenating reagent usually in the presence of asolvent. Halogenating reagents that can be used include phosphorusoxyhalides, phosphorus trihalides, phosphorus pentahalides, thionylchloride, dihalotrialkylphophoranes, dihalodiphenylphosphoranes, oxalylchloride and phosgene. Preferred are phosphorus oxyhalides andphosphorus pentahalides. To obtain complete conversion, at least 0.33equivalents of phosphorus oxyhalide versus the compound of Formula 4should be used, preferably between 0.33 and 1.2 equivalents. To obtaincomplete conversion, at least 0.20 equivalents of phosphorus pentahalideversus the compound of Formula 4 should be used, preferably betweenabout 0.20 and 1.0 equivalents. Compounds of Formula 4 wherein R³ isC₁-C₄ alkyl are preferred for this reaction.

[0070] Typical solvents for this halogenation include halogenatedalkanes, such as dichloromethane, chloroform, chlorobutane and the like,aromatic solvents, such as benzene, xylene, chlorobenzene and the like,ethers, such as tetrahydrofrran, p-dioxane, diethyl ether, and the like,and polar aprotic solvents such as acetonitrile, N,N-dimethylformamide,and the like. Optionally, an organic base, such as triethylamine,pyridine, N,N-dimethylaniline or the like, can be added. Addition of acatalyst, such as N,N-dimethylformamide, is also an option. Preferred isthe process in which the solvent is acetonitrile and a base is absent.Typically, neither a base nor a catalyst is required when acetonitrilesolvent is used. The preferred process is conducted by mixing thecompound of Formula 4 in acetonitrile. The halogenating reagent is thenadded over a convenient time and the mixture is then held at the desiredtemperature until the reaction is complete. The reaction temperature istypically between 20° C. and the boiling point of acetontrile, and thereaction time is typically less than 2 hours. The reaction mass is thenneutralized with an inorganic base, such as sodium bicarbonate, sodiumhydroxide and the like, or an organic base, such as sodium acetate. Thedesired product, a compound of Formula 1, can be isolated by methodsknown to those skilled in the art, including crystallization, extractionand distillation.

[0071] In step (2) the compound of Formula I wherein R³ is C₁-C₄ alkyl,an ester, can be hydrolyzed to a compound of Formula I wherein R³ is H,a carboxylic acid. The hydrolysis can be catalyzed by acids, metal ions,and by enzymes. Iodotrimethylsilane is noted as an example of an acidwhich can be used to catalyze the hydrolysis (see Advanced OrganicChemistry, Third Ed., Jerry March, John Wiley & Sons, Inc. New York,1985, pp. 334-338 for a review of methods). Base-catalyzed hydrolyticmethods are not recommended for the hydrolysis of compounds of Formula Iand can result in decomposition. The carboxylic acid can be isolated bymethods known to those skilled in the art, including crystallization,extraction and distillation.

[0072] In step (3) as illustrated in Scheme 3, a compound of Formula Iis treated with an oxidizing agent optionally in the presence of acid. Acompound of Formula I wherein R³ is C₁-C₄ alkyl (i.e. a preferredproduct of step (1)) is preferred as starting material for step (3). Theoxidizing agent can be hydrogen peroxide, organic peroxides, potassiumpersulfate, sodium persulfate, ammonium persulfate, potassiummonopersulfate (e.g., Oxone®) or potassium permanganate. To obtaincomplete conversion, at least one equivalent of oxidizing agent versusthe compound of Formula I should be used, preferably from about one totwo equivalents. This oxidation is typically carried out in the presenceof a solvent. The solvent can be an ether, such as tetrahydrofuran,p-dioxane and the like, an organic ester, such as ethyl acetate,dimethyl carbonate and the like, or a polar aprotic organic such asN,N-dimethylformamide, acetonitrile and the like. Acids suitable for usein the oxidation step include inorganic acids, such as sulfuric acid,phosphoric acid and the like, and organic acids, such as acetic acid,benzoic acid and the like. The acid, when used, should be used ingreater than 0.1 equivalents versus the compound of Formula I. To obtaincomplete conversion, one to five equivalents of acid can be used. Forthe compounds of Formula I wherein X is CR², the preferred oxidant ishydrogen peroxide and the oxidation is preferably carried out in theabsence of acid. For the compounds of Formula I wherein X is N, thepreferred oxidant is potassium persulfate and the oxidation ispreferably carried out in the presence of sulfuric acid. The reactioncan be carried out by mixing the compound of Formula I in the desiredsolvent and, if used, the acid. The oxidant can then be added at aconvenient rate. The reaction temperature is typically varied from aslow as about 0° C. up to the boiling point of the solvent in order toobtain a reasonable reaction time to complete the reaction, preferablyless than 8 hours. The desired product, a compound of Formula II whereinR³ is C₁-C₄ alkyl, can be isolated by methods known to those skilled inthe art, including crystallization, extraction and distillation.

[0073] In step (4) as illustrated in Scheme 4, a compound of Formula IIwherein R³ is C₁-C₄ alkyl, an ester, can be converted to a compound ofFormula II wherein R³ is H, a carboxylic acid. Methods for convertingesters to carboxylic acids are well known to those skilled in the art.Compounds of Formula II (R³ is C₁-C₄ alkyl) can be converted tocompounds of Formula II (R³ is H) by numerous methods includingnucleophilic cleavage under anhydrous conditions or hydrolytic methodsinvolving the use of either acids or bases (see T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley &Sons, Inc., New York, 1991, pp. 224-269 for a review of methods). Forthe method of Scheme 4, base-catalyzed hydrolytic methods are preferred.Suitable bases include alkali metal (such as lithium, sodium orpotassium hydroxides. For example, the ester can be dissolved in amixture of water and an alcohol such as ethanol. Upon treatment withsodium hydroxide or potassium hydroxide, the ester is saponified toprovide the sodium or potassium salt of the carboxylic acid.Acidification with a strong acid, such as hydrochloric acid or sulfuricacid, yields the carboxylic acid. The carboxylic acid can be isolated bymethods known to those skilled in the art, including crystallization,extraction and distillation.

[0074] It is noted that certain compounds of Formula I wherein R¹ ishalogen can be prepared from other compounds of Formula I wherein R¹ isa different halogen or is a sulfonate group such as p-toluenesulfonate,benzenesulfonate and methanesulfonate. For example, a compound ofFormula I wherein R¹ is Br can be prepared by treating with hydrogenbromide the corresponding compound of Formula I wherein R¹ is Cl orp-toluenesulfonate. The reaction is conducted in a suitable solvent suchas dibromomethane, dichloromethane or acetonitrile. The reaction can beconducted at or near atmospheric pressure or above atmospheric pressurein a pressure vessel. When R¹ in the starting compound of Formula I is ahalogen such as Cl, the reaction is preferably conducted in such a waythat the hydrogen halide generated from the reaction is removed bysparging or other suitable means. The reaction can be conducted betweenabout 0 and 100° C., most conveniently near ambient temperature (e.g.,about 10 to 40° C.), and more preferably between about 20 and 30° C.Addition of a Lewis acid catalyst (e.g., aluminum tribromide forpreparing Formula I wherein R¹ is Br) can facilitate the reaction. Theproduct of Formula I is isolated by the usual methods known to thoseskilled in the art, including extraction, distillation andcrystallization.

[0075] Starting compounds of Formula I wherein R¹ is halogen can beprepared as already described for Scheme 2. Starting compounds ofFormula I wherein R¹ is a sulfonate group can likewise be prepared fromcorresponding compounds of Formula 4 by standard methods such astreatment with a sulfonyl chloride (e.g., p-toluenesulfonyl chloride)and base such as a tertiary amine (e.g., triethylamine) in a suitablesolvent such as dichloromethane.

[0076] Without further elaboration, it is believed that one skilled inthe art using the preceding description can utilize the presentinvention to its fullest extent. The following Examples are, therefore,to be construed as merely illustrative, and not limiting of thedisclosure in any way whatsoever. The starting material for thefollowing Examples may not have necessarily been prepared by aparticular preparative run whose procedure is described in otherExamples. Percentages are by weight except for chromatographic solventmixtures or where otherwise indicated. Parts and percentages forchromatographic solvent mixtures are by volume unless otherwiseindicated. ¹H NMR spectra are reported in ppm downfield fromtetramethylsilane; “s” means singlet, “d” means doublet, “t” meanstriplet, “q” means quartet, “m” means multiplet, “dd” means doublet ofdoublets, “dt” means doublet of triplets, and “br s” means broadsinglet.

EXAMPLE 1 Preparation of Ethyl 5-Oxo-2-phenyl-3-pyrazolidinecarboxylate(alternatively named Ethyl 1-Phenyl-3-pyrazolidinone-5-carboxylate)using Diethyl Maleate

[0077] To a 300-mL four-necked flask equipped with a mechanical stirrer,thermometer, addition funnel, reflux condenser, and nitrogen inlet wascharged 80 mL of absolute ethanol, 80.0 mL (0.214 mol) of 21% sodiumethoxide in ethanol, and 20.0 mL (0.203 mol) of phenylhydrazine. Theorange solution was treated dropwise with 40.0 mL (0.247 mol) of diethylmaleate over a period of about 18 minutes. The temperature of thereaction mass rose from 25 to 38° C. during the first 5 minutes of theaddition. A water bath was used intermittently throughout the remainderof the addition to moderate the reaction temperature between 38-42° C.The resulting orange-red solution was held under ambient conditions for30 minutes. It was then added to a separatory funnel containing 20.0 mL(0.349 mol) of glacial acetic acid and 700 mL of water. The mixture wasextracted with 250 mL of dichloromethane. The extract was dried overmagnesium sulfate, filtered, and then concentrated on a rotaryevaporator. The resulting yellow-black oil (52.7 g) was diluted with 100mL of ether, whereupon crystallization of the product was rapid enoughto cause mild boiling. The slurry was held for 2 hours under ambientconditions. It was then cooled to about 0° C. The product was isolatedvia filtration, washed with 2×20 mL of cold ether, and then air-dried onthe filter for about 15 minutes. The product consisted of 29.1 g (61%)of a highly crystalline, white powder. No significant impurities wereobserved by ¹H NMR. The filtrate was concentrated to 20.8 g of a brownoil. Analysis of the oil showed the presence of an additional 6.4 g(13%) of the desired product. Hence, the overall yield of the reactionwas 74%.

[0078]¹H NMR (DMSO-d₆) δ 10.25 (s, 1H), 7.32 (t, 2H), 7.15 (d, 2H), 7.00(t, 1H), 4.61 (dd, 1H), 4.21 (q, 2H), 2.95 (dd, 1H), 2.45 (dd, 1H), 1.25(t, 3H).

EXAMPLE 2 Preparation of Ethyl 5-Oxo-2-phenyl-3-pyrazolidinecarboxylate(alternatively named Ethyl 1-Phenyl-3-pyrazolidinone-5-carboxylate)using Diethyl Fumarate

[0079] To a 500-mL four-necked flask equipped with a mechanical stirrer,thermometer, addition funnel, reflux condenser, and nitrogen inlet wascharged 150 mL of absolute ethanol, 15.0 g (0.212 mol) of 96% sodiumethoxide in ethanol, and 20.0 mL (0.203 mol) of phenylhydrazine. Theorange mixture was treated dropwise with 40.0 mL (0.247 mol) of diethylfumarate over a period of 75 minutes. The temperature of the reactionmass rose from 28 to a maximum of 37° C. during the addition, and thefinal temperature was 32° C. The resulting somewhat cloudy, orangesolution was held under ambient conditions for 135 minutes. The reactionmixture was then poured into a separatory funnel containing 15.0 mL(0.262 mol) of glacial acetic acid and 700 mL of water. The mixture wasextracted with 150 mL of dichloromethane. The extract was dried overmagnesium sulfate, filtered, and then concentrated on a rotaryevaporator. The resulting brown-yellow oil (41.3 g) was diluted with 100mL of ether. Several seed crystals were added. The mixture was held for30 minutes under ambient conditions. It was then cooled to about 0° C.The product was isolated via filtration, washed with 2×10 mL of coldether, and then air-dried on the filter for about 15 minutes. Theproduct consisted of 9.5 g (20%) of a highly crystalline, white powder.No significant impurities were observed by ¹H NMR. The filtrate wasconcentrated to 31 g of a brown oil. Analysis of the oil showed thepresence of an additional 7.8 g (16%) of the desired product. Hence, theoverall selectivity of the reaction was 36%.

EXAMPLE 3 Preparation of Ethyl5-Oxo-2-(2-pyridinyl-3-pyrazolidinecarboxylate (alternatively namedEthyl 1-(2-Pyridinyl-3-pyrazolidinone-5-carboxlate)

[0080] To a 200-mL four-necked flask equipped with a mechanical stirrer,thermometer, addition funnel, reflux condenser, and nitrogen inlet wascharged 18 mL of absolute ethanol, 18.0 mL (0.0482 mol) of 21% sodiumethoxide in ethanol, and 5.00 g (0.0458 mol) of 2-hydrazinopyridine. Thesolution was heated to 34° C. It was then treated dropwise with 9.0 mL(0.056 mol) of diethyl maleate over a period of 20 minutes. Thetemperature of the reaction mass rose to a maximum of 48° C. during theaddition. The resulting orange solution was held under ambientconditions for 85 minutes. It was then poured into a separatory funnelcontaining 4.0 mL (0.070 mol) of glacial acetic acid and 300 mL ofwater. The mixture was extracted with 2×50 mL of dichloromethane. Theextract was dried over magnesium sulfate, filtered, then concentrated ona rotary evaporator. The resulting orange oil (10.7 g) was subjected toflash chromatography on a column of 200 g of silica gel using 4%methanol in chloroform as the eluant (50 mL fractions). Fractions 9-12were evaporated on a rotary evaporator to give 3.00 g of an orange oilwhich contained 77% the desired product, 15% chloroform and 8% diethyl2-ethoxybutanedioate. Fractions 13-17 were concentrated to give 4.75 gof an orange-yellow oil which contained 94% the desired product and 6%chloroform. Fractions 18-21 were concentrated to give 1.51 g of anolive-green oil which contained 80% the desired product and 20%chloroform. Overall yield of the desired product was 8.0 g (74%).

[0081]¹H NMR (DMSO-d₆) δ 10.68 (br, 1H), 8.22 (d, 1H), 7.70 (t, 1H),6.90 (m, 2H), 5.33 (dd, 1H), 4.17 (q, 2H), 3.05 (dd, 1H), 2.48 (dd, 1H),1.21 (t, 3H).

EXAMPLE 4 Preparation of Ethyl 2-(2-Chlorophenyl-5-Oxo-3-pyrazolidinecarboxylate (alternatively named Ethyl1-(2-Chlorophenyl -3-pyrazolidinone-5-carboxylate)

[0082] To a 250-mL four-necked flask equipped with a mechanical stirrer,thermometer, addition funnel, reflux condenser, and nitrogen inlet wascharged 40 mL of absolute ethanol, 40.0 mL (0.107 mol) of 21% sodiumethoxide in ethanol, and 14.5 g (0.102 mol) of(2-chlorophenyl)hydrazine. The purple solution was heated to 35° C. Itwas then treated dropwise with 19.0 mL (0.117 mol) of diethyl maleateover a period of about 23 minutes. A water/ice bath was usedintermittently throughout the addition to moderate the reactiontemperature between 35-40° C. The reaction mixture was held at thistemperature for 30 minutes. It was then added to a separatory funnelcontaining 10.0 mL (0.175 mol) of glacial acetic acid and 400 mL ofwater. The mixture was extracted with 2×100 mL of dichloromethane. Theextract was dried over magnesium sulfate, filtered, and thenconcentrated on a rotary evaporator. The resulting dark brown oil (31.0g) crystallized upon standing. The material was suspended in 100 mL ofether and the slurry was stirred for about 1 hour. The product wasisolated by filtration, washed with 50 mL of ether, and then driedovernight at room temperature in vacuo. The product consisted of 12.5 g(46%) of a crystalline powder. No significant impurities were observedby ¹H NMR. The filtrate was concentrated to 16.3 g of a brown oil.Analysis of the oil showed the presence of an additional 6.7 g (25%) ofthe desired product. Hence, the overall selectivity of the reaction was71%.

[0083]¹H NMR (DMSO-d₆) δ 10.14 (s, 1H), 7.47 (6, 1H), 7.32 (m, 2H), 7.14(t, 1H), 4.39 (d, 1H), 4.19 (q, 2H), 3.07 (dd, 1H), 2.29 (d, 1H), 1.22(t, 3H).

EXAMPLE 5 Preparation of Ethyl2-(3-Chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (alternativelynamed Ethyl 1-(3-Chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate)

[0084] To a 2-L four-necked flask equipped with a mechanical stirrer,thermometer, addition funnel, reflux condenser, and nitrogen inlet wascharged 250 mL of absolute ethanol and 190 mL (0.504 mol) of 21% sodiumethoxide in ethanol. The mixture was heated to reflux at about 83° C. Itwas then treated with 68.0 g (0.474 mol) of 3-chloro-2(1H)-pyridinonehydrazone (alternatively named 3-chloro-2-hydrazinopyridine). Themixture was re-heated to reflux over a period of 5 minutes. The yellowslurry was then treated dropwise with 88.0 mL (0.544 mol) of diethylmaleate over a period of 5 minutes. The boil-up rate increased markedlyduring the addition. By the end of the addition all of the startingmaterial had dissolved. The resulting orange-red solution was held atreflux for 10 minutes. After being cooled to 65° C., the reactionmixture was treated with 50.0 mL (0.873 mol) of glacial acetic acid. Aprecipitate formed. The mixture was diluted with 650 mL of water,whereupon the precipitate dissolved. The orange solution was cooled inan ice bath. Product began to precipitate at 28° C. The slurry was heldat about 2° C. for 2 hours. The product was isolated via filtration,washed with 3×50 mL of 40% aqueous ethanol, and then air-dried on thefilter for about 1 hour. The product consisted of 70.3 g (55%) of ahighly crystalline, light orange powder. No significant impurities wereobserved by ¹H NMR.

[0085]¹H NMR (DMSO-d₆) δ 0.18 (s, 1H), 8.27 (d, 1H), 7.92 (d, 1H), 7.20(dd, 1H), 4.84 (d, 1H), 4.20 (q, 2H), 2.91 (dd, 1H), 2.35 (d, 1H), 1.22(t, 3H).

EXAMPLE 6 Preparation of Ethyl3-Chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate (alternativelynamed Ethyl 1-Phenyl-3-chloro-2-pyrazoline-5-carboxylate) EXAMPLE 6AUsing Phosphorus Oxychloride in Acetonitrile in Absence of Base

[0086] To a 500-mL four-necked flask equipped with a mechanical stirrer,thermometer, addition funnel, reflux condenser, and nitrogen inlet wascharged 150 mL of acetonitrile, 25.0 g (0.107 mol) of ethyl5-oxo-2-phenyl-3-pyrazolidinecarboxylate, and 11.0 mL (0.118 mol) ofphosphorus oxychloride. The light-yellow solution was heated to 78-80°C. for a period of 45 minutes. After being cooled to 54° C., theresulting, deep blue-green mixture was treated dropwise with a solutionof 25.0 g (0.298 mol) of sodium bicarbonate in 250 mL of water. Anorange oil separated during the 15-minute addition. After being stirredfor about 5 minutes, the pH of the mixture was about 1. An additional10.0 g (0.119 mol) of sodium bicarbonate were added as a solid over aperiod of about 3 minutes, resulting in a final pH of about 6. Themixture was diluted with 400 mL of water, whereupon the orange oilcrystallized. The crystalline mass was broken up with a spatula. Theproduct was isolated via filtration, washed with 4×100 mL of water, andthen air-dried on the filter for about 2 hours. The product consisted of24.5 g (91%) of a fluffy, crystalline, light yellow powder. Nosignificant impurities were observed by ¹H NMR.

[0087]¹H NMR (DMSO-d₆) δ 2.74 (t, 2H), 6.88 (d, 2H), 6.83 (t, 1H), 5.02(dd, 1H), 4.14 (q, 2H), 3.68 (dd, 1H), 3.34 (d, 1H), 1.16 (t, 3H).

EXAMPLE 6B Using Phosphorus Oxychloride in Chloroform in Absence of Base

[0088] To a 100-mL two-necked flask equipped with a magnetic stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 50 mL ofchloroform, 5.00 g (0.0213 mol) of ethyl5-oxo-2-phenyl-3-pyrazolidinecarboxylate, 2.10 mL (0.0225 mol) ofphosphorus oxychloride, and 2 drops of N,N-dimethylformamide. Thered-orange solution was heated to reflux at 64° C. over a period of 60minutes. The resulting mixture, a yellow-brown liquid and deep green,gummy solids, was held at reflux for 140 minutes. It was then dilutedwith 100 mL of dichloromethane and transferred to a separatory funnel.The solution was washed twice with 50 mL of 6% aqueous sodiumbicarbonate. The organic layer was dried over magnesium sulfate,filtered, then concentrated on a rotary evaporator. The crude productconsisted of 1.50 g of an orange oil, which crystallized upon standing.Analysis of the crude product by ¹H NMR showed it to be about 65% thedesired product and 35% starting material. The yield of the desiredproduct was therefore about 18%.

EXAMPLE 6C Using Phosphorus Oxychloride in Chloroform in Presence ofTriethylamine

[0089] To a 100-mL two-necked flask equipped with a magnetic stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 20 mL ofchloroform, 2.00 g (0.00854 mol) of ethyl5-oxo-2-phenyl-3-pyrazolidinecarboxylate, 1.30 mL (0.00933 mol) oftriethylamine, 2 drops of N,N-dimethylformamide, and 0.0850 mL (0.00912mol) of phosphorus oxychloride. An immediate and vigorous reaction tookplace when the phosphorus oxychloride was added. The mixture was heatedto reflux at 64° C. for 25 minutes. The resulting yellow solution wasdiluted with 50 mL of water and then treated with 3.0 g (0.036 mol) ofsolid sodium bicarbonate. The two-phase mixture was stirred for 50minutes under ambient conditions. It was then transferred to aseparatory funnel and diluted with 100 mL of dichloromethane. Theorganic layer was separated and then washed in turn with 50 mL of 5.5%aqueous hydrochloric acid and 50 mL of 3.8% aqueous sodium carbonate.The washed, organic layer was dried over magnesium sulfate, filtered,and then concentrated on a rotary evaporator. The crude productconsisted of 1.90 g of a yellow oil, which crystallized upon standing.Analysis of the crude product by ¹H NMR showed it to be about 94% thedesired product, 2% starting material and 2% an unidentified impurity.The yield of the desired product was therefore about 83%.

EXAMPLE 7 Preparation of Ethyl3-Chloro-4,5-dihydro-1-(2-pyridinyl)-1H-pyrazole-5-carboxylate(alternatively named Ethyl1-(2-Pyridinyl)-3-chloro-2-pyrazoline-5-carboxylate)

[0090] To a 250-mL four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 50 mL ofacetonitrile, 4.70 g (0.0188 mol) of5-oxo-2-(2-pyridinyl)-3-pyrazolidinecarboxylate, and 2.00 mL (0.0215mol) of phosphorus oxychloride. The mixture self-heated from 22 to 33°C. After being held for 60 minutes under ambient conditions, a samplewas taken. Analysis by ¹H NMR showed a 70% conversion of the startingmaterial to the desired product. The mixture was heated to reflux at 85°C. for 80 minutes. The heating mantle was removed. The resultingyellow-orange solution was diluted with 50 mL of water. It was thentreated dropwise with 3.9 g (0.049 mol) of 50% aqueous caustic,resulting in a pH of about 7.5. After being stirred for 20 minutes, thepH of the mixture had dropped to about 3. An additional 3.0 g (0.038mol) of 50% aqueous caustic were added, whereupon the pH increased toabout 9.0. A small amount of concentrated hydrochloric acid was added toadjust the pH to about 7.5. The neutralized mixture was transferred to aseparatory funnel containing 300 mL of water and 100 mL ofdichloromethane. The organic layer was separated, dried over magnesiumsulfate, filtered, and then concentrated on a rotary evaporator. Theproduct consisted of 4.10 g (84%) of a pale yellow oil, whichcrystallized upon standing. The only appreciable impurities observed by¹H NMR were 1.0% starting material and 0.6% acetonitrile.

[0091]¹H NMR (DMSO-d₆) δ 8.18 (d, 1H), 8.63 (t, 1H), 8.13 (d, 1H), 7.80(t, 1H), 5.08 (dd, 1H), 4.11 (m, 2H), 3.65 (dd, 1H), 3.27 (dd, 1H), 1.14(t, 3H).

EXAMPLE 8 Preparation of Ethyl3-Chloro-1-(3-chloro-2-pyridinyl)-4,5-hydro-1H-pyrazole-5-carboxlate(alternatively named Ethyl1-(3-Chloro-2-pyridinyl)-3-chloro-2-pyrazoline-5-carboxylate)

[0092] To a 2-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 1000 mL ofacetonitrile, 91.0 g (0.337 mol) of ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate, and 35.0 mL(0.375 mol) of phosphorus oxychloride. Upon adding the phosphorusoxychloride, the mixture self-heated from 22 to 25° C. and a precipitateformed. The light-yellow slurry was heated to reflux at 83° C. over aperiod of 35 minutes, whereupon the precipitate dissolved. The resultingorange solution was held at reflux for 45 minutes, whereupon it hadbecome black-green. The reflux condenser was replaced with adistillation head, and 650 mL of solvent was removed by distillation. Asecond 2-L four-necked flask equipped with a mechanical stirrer wascharged with 130 g (1.55 mol) of sodium bicarbonate and 400 mL of water.The concentrated reaction mixture was added to the sodium bicarbonateslurry over a period of 15 minutes. The resulting, two-phase mixture wasstirred vigorously for 20 minutes, at which time gas evolution hadceased. The mixture was diluted with 250 mL of dichloromethane and thenwas stirred for 50 minutes. The mixture was treated with 11 g of Celite545® diatomaceous earth and then filtered to remove a black, tarrysubstance that inhibited phase separation. Since the filtrate was slowto separate into distinct phases, it was diluted with 200 mL ofdichloromethane and 200 mL of water and treated with another 15 g ofCelite 545®. The mixture was filtered, and the filtrate was transferredto a separatory funnel. The heavier, deep green organic layer wasseparated. A 50 mL rag layer was refiltered and then added to theorganic layer. The organic solution (800 mL) was treated with 30 g ofmagnesium sulfate and 12 g of silica gel and the slurry was stirredmagnetically for 30 minutes. The slurry was filtered to remove themagnesium sulfate and silica gel, which had become deep blue-green. Thefilter cake was washed with 100 mL of dichloromethane. The filtrate wasconcentrated on a rotary evaporator. The product consisted of 92.0 g(93%) of a dark amber oil. The only appreciable impurities observed by¹H NMR were 1% starting material and 0.7% acetonitrile.

[0093]¹H NMR (DMSO-d₆) δ 8.12 (d, 1H), 7.84 (d, 1H), 7.00 (dd, 1H), 5.25(dd, 1H), 4.11 (q, 2H), 3.58 (dd, 1H), 3.26 (dd, 1H), 1.15 (t, 3H).

EXAMPLE 9 Preparation of Ethyl3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(alternatively named Ethyl1-(3-Chloro-2-pyridinyl)-3-bromo-2-pyrazoline-5-carboxylate) EXAMPLE 9AUsing Phosphorus Oxybromide

[0094] To a 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 400 mL ofacetonitrile, 50.0 g (0.185 mol) of ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate, and 34.0 g(0.119 mol) of phosphorus oxybromide. The orange slurry was heated toreflux at 83° C. over a period of 20 minutes. The resulting turbid,orange solution was held at reflux for 75 minutes, at which time adense, tan, crystalline precipitate had formed. The reflux condenser wasreplaced with a distillation head, and 300 mL of a cloudy, colorlessdistillate was collected. A second 1-L four-necked flask equipped with amechanical stirrer was charged with 45 g (0.54 mol) of sodiumbicarbonate and 200 mL of water. The concentrated reaction mixture wasadded to the sodium bicarbonate slurry over a period of 5 minutes. Theresulting, two-phase mixture was stirred vigorously for 5 minutes, atwhich time gas evolution had ceased. The mixture was diluted with 200 mLof dichloromethane, and then was stirred for 75 minutes. The mixture wastreated with 5 g of Celite 545®, and then filtered to remove a brown,tarry substance. The filtrate was transferred to a separatory funnel.The brown organic layer (400 mL) was separated, and then was treatedwith 15 g of magnesium sulfate and 2.0 g of Darco G60 activatedcharcoal. The resulting slurry was stirred magnetically for 15 minutesand then filtered to remove the magnesium sulfate and charcoal. Thegreen filtrate was treated with 3 g of silica gel and stirred forseveral minutes. The deep blue-green silica gel was removed byfiltration and the filtrate was concentrated on a rotary evaporator. Theproduct consisted of 58.6 g (95%) of a light amber oil, whichcrystallized upon standing. The only appreciable impurity observed by ¹HNMR was 0.3% acetonitrile.

[0095]¹H NMR (DMSO-d₆) δ 8.12 (d, 1H), 7.84 (d, 1H), 6.99 (dd, 1H), 5.20(dd, 1H), 4.11 (q, 2H), 3.60 (dd, 1H), 3.29 (dd, 1H), 1.15 (t, 3H).

EXAMPLE 9B Using Phosphorus Pentabromide

[0096] To a 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 330 mL ofacetonitrile, 52.0 g (0.193 mol) of ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate, and 41.0 g(0.0952 mol) of phosphorus pentabromide. The orange slurry was heated toreflux at 84° C. over a period of 20 minutes. The resulting brick-redmixture was held at reflux for 90 minutes, at which time a dense, tan,crystalline precipitate had formed. The reflux condenser was replacedwith a distillation head, and 220 mL of a cloudy, colorless distillatewas collected. A second 1-L four-necked flask equipped with a mechanicalstirrer was charged with 40 g (0.48 mol) of sodium bicarbonate and 200mL of water. The concentrated reaction mixture was added to the sodiumbicarbonate slurry over a period of 5 minutes. The resulting, two-phasemixture was stirred vigorously for 10 minutes, at which time gasevolution had ceased. The mixture was diluted with 200 mL ofdichloromethane, and then was stirred for 10 minutes. The mixture wastreated with 5 g of Celite 545®, and then filtered to remove a purple,tarry substance. The filter cake was washed with 50 mL ofdichloromethane. The filtrate was transferred to a separatory funnel.The purple-red organic layer (400 mL) was separated, then was treatedwith 15 g of magnesium sulfate and 2.2 g of Darco G60 activatedcharcoal. The slurry was stirred magnetically for 40 minutes. The slurrywas filtered to remove the magnesium sulfate and charcoal. The filtratewas concentrated on a rotary evaporator. The product consisted of 61.2 g(95%) of a dark amber oil, which crystallized upon standing. The onlyappreciable impurity observed by ¹H NMR was 0.7% acetonitrile.

[0097]¹H NMR (DMSO-d₆) δ 8.12 (d, 1H), 7.84 (d, 1H), 6.99 (dd, 1H), 5.20(dd, 1H), 4.11 (q 2H), 3.60 (dd, 1H), 3.29 (dd, 1H), 1.15 (t, 3H).

EXAMPLE 10 Preparation of Ethyl3-Chloro-1-phenyl-1H-pyrazole-5-carboxylate (alternatively named Ethyl1-Phenyl-3-chloropyrazole-5-carboxylate) EXAMPLE 10A Using HydrogenPeroxide

[0098] To a 100-mL two-necked flask equipped with a magnetic stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 1.50 g(0.00594 mol) of ethyl3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate and 15 mL ofacetonitrile. The mixture was heated to 80° C. It was then treated with0.700 mL (0.00685 mol) of 30% aqueous hydrogen peroxide. The mixture washeld at 78-80° C. for 5 hours. The reaction mass was then added to 70 mLof water. The precipitated product was isolated via filtration, and thenwashed with 15 mL of water. The wet cake was dissolved in 100 mL ofdichloromethane. The solution was dried over magnesium sulfate,filtered, and then concentrated on a rotary evaporator. The productconsisted of 1.24 g (about 79%) of an orange oil, which crystallizedupon standing. The product was about 95% pure based upon ¹H NMR. ¹H NMR(DMSO-d₆) δ 7.50 (s, 5H), 7.20 (s, 1H), 7.92 (d, 1H), 4.18 (q, 2H), 1.14(t, 3H).

EXAMPLE 10B Using Manganese Dioxide

[0099] To a 100-mL two-necked flask equipped with a magnetic stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 3.00 g(0.0119 mol) of ethyl3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate, 25 mL ofchloroform, and 2.50 g (0.0245 mol) of activated manganese dioxide. Themixture was heated to reflux at 62° C. for a period of 1 hour. Analysisof a sample of the reaction mass by ¹H NMR showed about 6% conversion ofthe starting material to mainly the desired ethyl1-phenyl-3-chloropyrazole-5-carboxylate. The mixture was held foranother 5 hours at reflux. Analysis of a second sample showed about 9%conversion.

EXAMPLE 10C Using Sodium Hypochlorite

[0100] To a 100-mL two-necked flask equipped with a magnetic stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 1.00 g(0.00396 mol) of ethyl3-chloro-4,5-dihydro-1-phenyl-1H-pyrazole-5-carboxylate, 10 mL ofacetonitrile, 0.55 g (0.0040 mol) of sodium dihydrogen phosphatemonohydrate, and 5.65 g (0.00398 mol) of 5.25% aqueous sodiumhypochlorite. The orange solution was held under ambient conditions for85 minutes. Analysis of a sample of the reaction mass by ¹H NMR showedabout 71% conversion of the starting material to two main products. Thesolution was heated to 60° C. for 60 minutes. Analysis of a secondsample showed no increase in conversion from the first sample. Thereaction mixture was treated with an additional 3.00 g (0.00211 mol) of5.25% aqueous sodium hypochlorite. After being held for 60 minutes at60° C., the reaction mass was added to 100 mL of water. The mixture wasextracted with 100 mL of dichloromethane. The extract was separated,dried over magnesium sulfate, filtered, and then concentrated on arotary evaporator. The crude product consisted of 0.92 g of a red-orangeoil. ¹H NMR showed the crude product to consist mainly of ethyl3-chloro-1-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(4-chlorophenyl)-3-chloro-2-pyrazoline-5-carboxylate) and ethyl3-chloro-1-(2-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(2-chlorophenyl)-3-chloro-2-pyrazoline-5-carboxylate) in a ratio of2:1. The isomer could be separated by chromatography on silica gel using10% ethyl acetate in hexanes as the eluant.

[0101]¹H NMR for ethyl3-chloro-1-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(DMSO-d₆) δ 7.28 (d, 2H), 6.89 (d, 2H), 5.08 (dd, 1H), 4.14 (q, 2H),3.71 (dd, 1H) 3.37 (dd, 1H), 1.16 (t,3H). ¹H NMR for ethyl3-chloro-1-(2-chlorophenyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(DMSO-d₆) δ 7.41 (d, 1H), 7.30 (m, 2H), 7.14 (m, 1H), 5.22 (dd, 1H),3.90 (q, 2H), 3.68 (dd, 1H), 3.38 (dd, 1H), 0.91 (t, 3H).

EXAMPLE 11 Preparation of Ethyl3-Chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate(alternatively named Ethyl1-(3-Chloro-2-pyridinyl)-3-chloropyrazole-5-carboxylate)

[0102] To a 2-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 99.5 g(0.328 mol) of 95% pure ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate,1000 mL of acetonitrile and 35.0 mL (0.661 mol) of 98% sulfuric acid.The mixture self-heated from 22 to 35° C. upon adding the sulfuric acid.After being stirred for several minutes, the mixture was treated with140 g (0.518 mol) of potassium persulfate. The slurry was heated toreflux at 84° C. for 4.5 hours. The resulting orange slurry was filteredwhile still warm (50-65° C.) to remove a fine, white precipitate. Thefilter cake was washed with 50 mL of acetonitrile. The filtrate wasconcentrated to about 500 mL on a rotary evaporator. A second 2-Lfour-necked flask equipped with a mechanical stirrer was charged with1250 mL of water. The concentrated reaction mass was added to the waterover a period of about 5 minutes. The product was isolated viafiltration, washed with 3×125 mL of 25% aqueous acetonitrile, washedonce with 100 mL of water, and then dried overnight in vacuo at roomtemperature. The product consisted of 79.3 g (82%) of a crystalline,orange powder. The only appreciable impurities observed by ¹H NMR wereabout 1.9% water and 0.6% acetonitrile.

[0103]¹H NMR (DMSO-d₆) δ 8.59 (d, 1H), 8.38 (d, 1H), 7.71 (dd, 1H), 7.31(s, 1H), 4.16 (q, 2H), 1.09 (t, 3H).

EXAMPLE 12 Preparation of Ethyl3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate(alternatively named Ethyl1-(3-Chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylate)

[0104] To a 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged 40.2 g(0.121 mol) of ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate,300 mL of acetonitrile and 13.0 mL (0.245 mol) of 98% sulfuric acid. Themixture self-heated from 22 to 36° C. upon adding the sulfuric acid.After being stirred for several minutes, the mixture was treated with48.0 g (0.178 mol) of potassium persulfate. The slurry was heated toreflux at 84° C. for 2 hours. The resulting orange slurry was filteredwhile still warm (50-65° C.) to remove a white precipitate. The filtercake was washed with 2×50 mL of acetonitrile. The filtrate wasconcentrated to about 200 mL on a rotary evaporator. A second 1-Lfour-necked flask equipped with a mechanical stirrer was charged with400 mL of water. The concentrated reaction mass was added to the waterover a period of about 5 minutes. The product was isolated viafiltration, washed with 100 mL of 20% aqueous acetonitrile, washed with75 mL of water, and then air-dried on the filter for 1 hour. The productconsisted of 36.6 g (90%) of a crystalline, orange powder. The onlyappreciable impurities observed by ¹H NMR were about 1% of an unknownand 0.5% acetonitrile.

[0105]¹H NMR (DMSO-d₆) δ 8.59 (d, 1H), 8.39 (d, 1H), 7.72 (dd, 1H), 7.35(s, 1H), 4.16 (q, 2H), 1.09 (t, 3H).

EXAMPLE 13 Preparation of3-Chloro-1-(3-chloro-2-pyridinyl-1H-pyrazole-5-carboxylic acid(alternatively named1-(3-Chloro-2-pyridinyl-3-chloropyrazole-5-carboxylic acid)

[0106] To a 1-L four-necked flask equipped with a mechanical stirrer,thermometer, and nitrogen inlet was charged 79.3 g (0.270 mol) of 97.5%ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate, 260mL of methanol, 140 mL of water, and 13.0 g (0.325 mol) of sodiumhydroxide pellets. The mixture self-heated from 22 to 35° C. and thestarting material began to dissolve upon adding the sodium hydroxide.After being stirred for 45 minutes under ambient conditions, all of thestarting material had dissolved. The resulting deep orange-brownsolution was concentrated to about 250 mL on a rotary evaporator. Theconcentrated reaction mixture was then diluted with 400 mL of water. Theaqueous solution was extracted with 200 mL of ether. The aqueous layerwas transferred to a 1-L Erlenmeyer flask equipped with a magneticstirrer. The solution was then treated dropwise with 36.0 g (0.355 mol)of concentrated hydrochloric acid over a period of about 10 minutes. Theproduct was isolated via filtration, reslurried with 2×200 mL of water,cover washed once with 100 mL of water, and then air-dried on the filterfor 1.5 hours. The product consisted of 58.1 g (83%) of a crystalline,light brown powder. About 0.7% ether was the only appreciable impurityobserved by ¹H NMR.

[0107]¹H NMR (DMSO-d₆) δ 13.95 (brs, 1H), 8.56 (d, 1H), 8.25 (d, 1H),7.68 (dd, 1H), 7.20 (s, 1H).

EXAMPLE 14 Preparation of3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-carboxylic acid(alternatively named 1-(3-Chloro-2-pyridinyl-3-bromopyrazole-5-carboxylic acid)

[0108] To a 300-mL four-necked flask equipped with a mechanical stirrer,thermometer, and nitrogen inlet was charged 25.0 g (0.0756 mol) of 98.5%pure ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate,75 mL of methanol, 50 mL of water, and 3.30 g (0.0825 mol) of sodiumhydroxide pellets. The mixture self-heated from 29 to 34° C. and thestarting material began to dissolve upon adding the sodium hydroxide.After being stirred for 90 minutes under ambient conditions, all of thestarting material had dissolved. The resulting dark orange solution wasconcentrated to about 90 mL on a rotary evaporator. The concentratedreaction mixture was then diluted with 160 mL of water. The aqueoussolution was extracted with 100 mL of ether. The aqueous layer wastransferred to a 500-mL Erlenmeyer flask equipped with a magneticstirrer. The solution was then treated dropwise with 8.50 g (0.0839 mol)of concentrated hydrochloric acid over a period of about 10 minutes. Theproduct was isolated via filtration, reslurried with 2×40 mL of water,cover washed once with 25 mL of water, and then air-dried on the filterfor 2 hours. The product consisted of 20.9 g (91%) of a crystalline, tanpowder. The only appreciable impurities observed by ¹H NMR were about0.8% of an unknown and 0.7% ether.

[0109]¹H NMR (DMSO-d₆) δ 13.95 (br s, 1H), 8.56 (d, 1H), 8.25 (d, 1H),7.68 (dd, 1H), 7.25 (s, 1H).

EXAMPLE 15 Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl-4,5-dihydro-1H-pyrazole-5-carboxylatefrom ethyl3-chloro-1-(3-chloro-2-pyridinyl)4.5-dihydro-1H-pyrazole-5-carboxylateusing hydrogen bromide

[0110] Hydrogen bromide was passed through a solution of ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(8.45 g, 29.3 mmol) in dibromomethane (85 mL). After 90 minutes the gasflow was terminated, and the reaction mixture was washed with aqueoussodium bicarbonate solution (100 mL). The organic phase was dried andevaporated under reduced pressure to give the title product as an oil(9.7 g, 99% yield), which crystallized on standing.

[0111]¹H NMR (CDCl₃) δ 8.07 (dd, J=1.6, 4.8 Hz, 1H), 7.65 (dd, J=1.6,7.8 Hz, 1H), 6.85 (dd, J=4.7, 7.7 Hz, 1H), 5.25 (X of ABX, 1H, J=9.3,11.9 Hz), 4.18 (q, 2H), 3.44 (1/2 of AB in ABX pattern, J=11.7, 17.3 Hz,1H), 3.24 (1/2 of AB in ABX pattern, J=9.3, 17.3 Hz, 1H), 1.19 (t, 3H).

[0112] The following Example 16 illustrates the preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate,which can be used to prepare ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylateby procedures similar to that described in Example 15.

EXAMPLE 16

[0113] Preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate

[0114] Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixtureof ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (10.0g, 37.1 mmol) and p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) indichloromethane (100 mL) at 0° C. Further portions of p-toluenesulfonylchloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) wereadded. The reaction mixture was then allowed to warm to room temperatureand was stirred overnight. The mixture was then diluted withdichloromethane (200 mL) and washed with water (3×70 mL). The organicphase was dried and evaporated to leave the title product as an oil(13.7 g, 87% yield), which slowly formed crystals. Productrecrystallized from ethyl acetate/hexanes melted at 99.5-100° C.

[0115] IR(nujol): 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178,1084, 1027, 948, 969, 868, 845 cm⁻¹.

[0116]¹H NMR (CDCl₃) δ 8.01 (dd, J=1.4, 4.6 Hz, 1H), 7.95 (d, J=8.4 Hz,2H), 7.56 (dd, J=1.6, 7.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 6.79 (dd,J=4.6, 7.7 Hz, 1H), 5.72 (X of ABX, J=9, 11.8 Hz, 1H), 4.16 (q, 2H),3.33 (1/2 of AB in ABX pattern, J=17.5, 11.8 Hz, 1H), 3.12 (1/2 of AB inABX pattern, J=17.3,9 Hz, 1H), 2.45 (s, 3H), 1.19 (t,3H).

[0117] By the procedures described herein together with methods known inthe art, the following compounds of Tables 1 to 3 can be prepared. Thefollowing abbreviations are used in the Tables: t is tertiary, s issecondary, n is normal, i is iso, Me is methyl, Et is ethyl, Pr ispropyl, i-Pr is isopropyl and t-Bu is tertiary butyl. TABLE 1

X is N X is CH X is CCl X is CBr R² R³ R² R³ R² R³ R² R³ R² R³ R² R³ R²R³ R² R³ R¹ is Cl Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me ClMe Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et ClEt Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-PrCl i-Pr Br i-Pr Cl i-Pr Br i-Pr Cl i-Pr Br i-Pr Cl i-Pr Br i-Pr Cl n-BuBr n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl i-Bu Br i-BuCl i-Bu Br i-Bu Cl i-Bu Br i-Bu Cl i-Bu Br i-Bu Cl s-Bu Br s-Bu Cl s-BuBr s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-BuCl t-Bu Br t-Bu Cl t-Bu Br t-Bu R¹ is Br Cl H Br H Cl H Br H Cl H Br HCl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et ClEt Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-PrBr n-Pr Cl n-Pr Br n-Pr Cl i-Pr Br i-Pr Cl i-Pr Br i-Pr Cl i-Pr Br i-PrCl i-Pr Br i-Pr Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-BuBr n-Bu Cl i-Bu Br i-Bu Cl i-Bu Br i-Bu Cl i-Bu Br i-Bu Cl i-Bu Br i-BuCl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl t-BuBr t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu

[0118] TABLE 2

X is N X is CH X is CCl X is CBr R² R³ R² R³ R² R³ R² R³ R² R³ R² R³ R²R³ R² R³ R¹ is Cl Cl H Br H Cl H Br H Cl H Br H Cl H Br H Cl Me Br Me ClMe Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et Cl Et Br Et Cl Et Br Et ClEt Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-Pr Br n-PrCl i-Pr Br i-Pr Cl i-Pr Br i-Pr Cl i-Pr Br i-Pr Cl i-Pr Br i-Pr Cl n-BuBr n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl i-Bu Br i-BuCl i-Bu Br i-Bu Cl i-Bu Br i-Bu Cl i-Bu Br i-Bu Cl s-Bu Br s-Bu Cl s-BuBr s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-BuCl t-Bu Br t-Bu Cl t-Bu Br t-Bu R¹ is Br Cl H Br H Cl H Br H Cl H Br HCl H Br H Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Me Br Me Cl Et Br Et ClEt Br Et Cl Et Br Et Cl Et Br Et Cl n-Pr Br n-Pr Cl n-Pr Br n-Pr Cl n-PrBr n-Pr Cl n-Pr Br n-Pr Cl i-Pr Br i-Pr Cl i-Pr Br i-Pr Cl i-Pr Br i-PrCl i-Pr Br i-Pr Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-Bu Br n-Bu Cl n-BuBr n-Bu Cl i-Bu Br i-Bu Cl i-Bu Br i-Bu Cl i-Bu Br i-Bu Cl i-Bu Br i-BuCl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl s-Bu Br s-Bu Cl t-BuBr t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu Cl t-Bu Br t-Bu

[0119] TABLE 3

R² R³ R² R³ R² R³ R² R³ R² R³ R² R³ Cl H Cl n-Pr Cl i-Bu Br H Br n-Pr Bri-Bu Cl Me Cl i-Pr Cl s-Bu Br Me Br i-Pr Br s-Bu Cl Et Cl n-Bu Cl t-BuBr Et Br n-Bu Br t-Bu

[0120] Utility

[0121] The compounds of Formulae I, I and 4 are useful as syntheticintermediates for preparing a compound of Formula III

[0122] wherein X, R¹, R² and n are defined as above; R⁶ is CH₃, Cl orBr; R⁷ is F, Cl, Br, I or CF₃; and R⁸ is C₁-C₄ alkyl.

[0123] Compounds of Formula III are useful as insecticides.

[0124] Compounds of Formula III can be prepared from compounds ofFormula II (and in turn from compounds of Formula 4 and I) by theprocesses outlined in Schemes 5-7.

[0125] Coupling of a pyrazolecarboxylic acid of Formula IIa (a compoundof Formula II wherein R³ is H) with an anthranilic acid of Formula 5provides the benzoxazinone of Formula 6. In Scheme 5, a benzoxazinone ofFormula 6 is prepared directly via sequential addition ofmethanesulfonyl chloride in the presence of a tertiary amine such astriethylamine or pyridine to a pyrazolecarboxylic acid of Formula IIa,followed by the addition of an anthranilic acid of Formula 5, followedby a second addition of tertiary amine and methanesulfonyl chloride.This procedure generally affords good yields of the benzoxazinone.

[0126] Scheme 6 depicts an alternate preparation for benzoxazinones ofFormula 6 involving coupling of a pyrazole acid chloride of Formula 8with an isatoic anhydride of Formula 7 to provide the Formula 6benzoxazinone directly.

[0127] Solvents such as pyridine or pyridine/acetonitrile are suitablefor this reaction. The acid chlorides of Formula 8 are available fromthe corresponding acids of Formula IIa by known procedures such aschlorination with thionyl chloride or oxalyl chloride.

[0128] Compounds of Formula III can be prepared by the reaction ofbenzoxazinones of Formula 6 with C₁-C₄ alkyl amines as outlined inScheme 7. The reaction can be run neat or in a variety of suitablesolvents including tetrahydrofuran, diethyl ether, dichloromethane orchloroform with optimum temperatures ranging from room temperature tothe reflux temperature of the solvent. The general reaction ofbenzoxazinones with amines to produce anthranilamides is well documentedin the chemical literature. For a review of benzoxazinone chemistry seeJakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103and references cited within. See also Coppola, J. Heterocyclic Chemistry1999, 36, 563-588.

What is claimed is:
 1. A compound of Formula I

wherein R¹ is halogen; each R² is independently C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂,C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆cycloalkylamino, C₃-C₆ (alkyl)cycloalkylamino, C₂-C₄ alkylcarbonyl,C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; R³ is H or C₁-C₄ alkyl; Xis N or CR⁴; R⁴ is H or R²; and n is 0 to 3, provided when X is CH thenn is at least
 1. 2. A compound of claim 1 wherein n is 1 to
 3. 3. Acompound of claim 1 wherein R¹ is Cl or Br; each R² is independently Clor Br, and one R² is at the 3-position; and X is N.
 4. A method forpreparing a compound of claim 1 comprising (1) treating a compound ofFormula 4

wherein R³ is C₁-C₄ alkyl; with a halogenating agent to form a compoundof Formula I; and when preparing compounds of Formula I wherein R³ is H(2) converting the compound formed in (1) to a compound wherein R³ is H.5. The method of claim 4 wherein n is 1 to
 3. 6. The method of claim 4wherein R¹ is Cl or Br; each R² is independently Cl or Br, and one R² isat the 3-position; R³ is C₁-C₄ alkyl; and X is N.
 7. The method of claim6 wherein the halogenating agent is a phosphorus oxyhalide or aphosphorus pentahalide.
 8. The method of claim 7 wherein step (1) iscarried out in the absence of a base using acetonitrile as the solvent.9. A compound of Formula II

wherein R¹ is halogen; each R² is independently C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂,C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆cycloalkylamino, C₃-C₆ (alkyl)cycloalkylamino, C₂-C₄ alkylcarbonyl,C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; R³ is H or C₁-C₄ alkyl; Xis N or CR⁴; R⁴ is H or R²; and n is 0 to 3, provided when X is CH thenn is at least
 1. 10. A compound of claim 9 wherein n is 1 to
 3. 11. Acompound of claim 9 wherein R¹ is Cl or Br; each R² is independently Clor Br, and one R² is at the 3-position; and X is N.
 12. A method ofpreparing a compound of Formula II of claim 9 comprising (3) treating acompound of Formula I

with an oxidant, optionally in the presence of an acid, to form acompound of Formula II; and when a compound of Formula I wherein R³ isC₁-C₄ alkyl is used to prepare a compound of Formula II wherein R³ is H,(4) converting the compound formed in (3) to a compound of Formula IIwherein R³ is H.
 13. The method of claim 12 wherein n is 1 to
 3. 14. Themethod of claim 12 wherein the oxidant is hydrogen peroxide or apersulfate salt.
 15. The method of claim 14 wherein X is CR⁴; and theoxidant is hydrogen peroxide.
 16. The method of claim 14 wherein X is N;the oxidant is potassium persulfate; and step (3) is carried out in thepresence of sulfuric acid.
 17. The method of claim 12 wherein in FormulaI wherein R¹ is Cl or Br; each R² is independently Cl or Br, and one R²is at the 3-position; R³ is C₁-C₄ alkyl; and X is N.
 18. The method ofclaim 12 wherein the compound of Formula I is prepared by a methodcomprising (1) treating a compound of Formula 4

wherein R³ is C₁-C₄ alkyl; with a halogenating agent to form a compoundof Formula I; and when preparing compounds of Formula I wherein R³ is H(2) converting the compound formed in (1) to a compound wherein R³ is H.19. A compound of Formula 4

wherein each R² is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₃-C₆(alkyl)cycloalkylamino, C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; Xis N; R³ is H or C₁-C₄ alkyl; and n is 0 to 3, provided when X is CHthen n is at least
 1. 20. A compound of claim 19 wherein n is 1 to 3.21. A compound of claim 19 wherein each R² is independently Cl or Br,and one R² is at the 3-position.
 22. A method of preparing a compound ofFormula III

wherein R¹ is halogen; each R² is independently C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂,C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆cycloalkylamino, C₃-C₆ (alkyl)cycloalkylamino, C₂-C₄ alkylcarbonyl,C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; X is N or CR⁴; R⁴ is H, Clor Br; R⁶ is CH₃, Cl or Br; R⁷ is F, Cl, Br, I or CF₃; R⁸ is C₁-_(C) ₄alkyl and n is 0, 1, 2 or 3; provided when X is CH then n is at least 1;using a compound of Formula II

wherein R³ is H; characterized by: preparing said compound of Formula IIby the method of claim
 12. 23. The method of claim 22 wherein n is 1 to3.